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Antihypertrophic actions of NO-independent soluble guanylyl cyclase (sGC) ligands BAY 41-2272 and BAY 58-2667 in vitro

Background

Over the last decade, we have shown that cGMP, derived from bradykinin, nitric oxide (NO, both from endogenous and exogenous sources) or natriuretic peptides, is a potent inhibitor of cardiac hypertrophy, across isolated cardiomyocytes and intact hearts both ex vivo and in vivo. However, NO• bioavailability is reduced due to scavenging by ROS; furthermore, oxidation of sGC may result in sGC dysfunction (including loss of responsiveness to NO•). In the present study, we tested the hypothesis that the NO•-independent sGC stimulator BAY 41-2272 and the NO-independent sGC activator BAY 58-2667 elicit powerful antihypertrophic actions.

Materials and methods

Neonatal rat cardiomyocytes were incubated at 37°C in the presence of the hypertrophic stimulus, endothelin-1 (ET1, 60 nM) ± BAY 41-2272 or BAY 58-2667 (0.01–0.3 μM) for 48 h in serum-free conditions. Cardiomyocyte hypertrophy was assessed in live cells using conventional in vitro markers of hypertrophy, two dimensional area and cardiomyocyte de novo protein synthesis. Results were expressed as % paired control cardiomyocytes, mean ± SE.

Results

See Table 1.

Table 1 sGC ligands inhibit cardiomyocyte hypertrophy

Conclusion

These results provide evidence that BAY 41-2272 and BAY 58-2667 elicit concentration-dependent inhibition of cardiac hypertrophy in vitro, in the absence of confounding haemodynamic factors and even at low (submicromolar) concentrations. These novel NO•-independent sGC ligands thus potentially may serve as useful antihypertrophic agents in patients, independent of blood pressure.

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Correspondence to Rebecca Ritchie.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Ritchie, R., Irvine, J., Love, J. et al. Antihypertrophic actions of NO-independent soluble guanylyl cyclase (sGC) ligands BAY 41-2272 and BAY 58-2667 in vitro. BMC Pharmacol 9, P59 (2009). https://doi.org/10.1186/1471-2210-9-S1-P59

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Keywords

  • Nitric Oxide
  • Cardiac Hypertrophy
  • Guanylyl Cyclase
  • Cardiomyocyte Hypertrophy
  • Soluble Guanylyl Cyclase